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Therapeutic targeting of malarial placental cytoadherence

疟疾胎盘细胞粘附的治疗靶向

基本信息

批准号：
9097541
负责人：
CHANNE D GOWDA
金额：
$ 48.52万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2020-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9097541
关键词：
Adherence Adhesives Adult Affinity Africa Amino Acids Antibodies Area Binding Binding Sites Biological Assay Biological Process Carbohydrates Cell surface Cells Cessation of life Chondroitin Sulfate A Chondroitin Sulfate Proteoglycan Chondroitin Sulfates Clinical Development Disease Elements Erythrocyte Membrane Erythrocytes Family Fetus Fluorescence Anisotropy Functional disorder Future Glycosaminoglycans Goals Health Heparin Hybrids Immunity Indium Infant Infection Inflammation Inorganic Sulfates Knowledge Label Length Libraries Ligands Location Low Birth Weight Infant Malaria Measures Mediating Mothers Natural Products Newborn Infant Oligosaccharides Parasites Pattern Pharmaceutical Preparations Phenotype Placenta Plasmodium falciparum Plasmodium falciparum erythrocyte membrane protein 1 Positioning Attribute Preclinical Drug Evaluation Pregnancy Pregnant Women Prevention Protein Region Proteins Reagent Research Research Personnel Resistance Risk Screening Result Structure Structure-Activity Relationship Surface Testing Therapeutic Tissues Unspecified or Sulfate Ion Sulfates Vaccines Variant Woman Work base biochemical model density design drug development effective therapy extracellular fluorophore high throughput screening inhibitor/antagonist innovation insight interest member mimetics novel novel therapeutics placental malaria pregnant prevent receptor research study screening small molecule inhibitor sulfation therapeutic development therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Plasmodium falciparum infection during pregnancy results in placental malaria (PM). In Africa alone, ~25 million women yearly are at risk of developing PM, which causes ~100,000 infant and tens of thousand maternal deaths. Low birth weight is common in PM and these newborns are highly vulnerable to death from subsequent malaria or other infections. Although people in endemic areas will have acquired protective immunity against malaria by their adulthood, women are susceptible to severe malaria during pregnancy. This is due to the adherence in the placenta of an antigenically distinctive P. falciparum phenotype. So women who have never been pregnant have no immunity to this parasite phenotype. In their first and second pregnancies women infected with P. falciparum, the adherent parasites are selected in the placenta, grow rapidly, allowing infected red blood cells (RBCs) to accumulate to high density in the placenta. This results in inflammation and placental dysfunction, causing PM. An effective treatment to prevent or treat PM is essential, but is not currently available. The parasite exports a variant adhesive protein called VAR2CSA, a member of Plasmodium falciparum erythrocyte membrane protein 1 family, that is displayed on the erythrocyte surface. The ectodomain of VA2CSA mediates the binding of IRBCs to 12-mer motifs of the chondroitin 4-sulfate (C4S) moieties of the CSPG receptor in the placenta. Women who have acquired inhibitory anti-VAR2CSA antibodies during prior pregnancies are resistant to PM and deliver healthy babies, indicating that blocking of IRBC adherence is a suitable strategy to treat PM. However, VAR2CSA is a highly polymorphic and so, obtaining a viable vaccine requires rationale design based on the knowledge of conserved C4S-binding site. An alternative approach is to develop adherence-blocking inhibitors. Since VAR2CSA is on the IRBC surface and is accessible for even highly polar molecules, this is predicted to be highly promising strategy. Accordingly, the goals of this proposal are to: (i) chemically synthesize the C4S 12-mers containing two sulfate residues at specific positions and a library of chondroitin sulfate oligosaccharides of different size and sulfation patterns. This will enable us to identify the optimally binding oligosaccharide and critical interactions involved in VAR2CSA-C4S binding; (ii) Using the novel and sensitive C4S 12-mer-based fluorescence anisotropy assay that we have already developed, we will screen drug and glycosaminoglycan mimetic libraries to identify, by high-throughput screening, small molecule inhibitors that block VAR2CSA-C4S binding and validate the inhibitors by a cell-based assay (iii) characterize the C4S-binding sites in VAR2CSA to identify the interacting amino acid residues. The results are expected to provide critical information necessary for developing therapeutics for PM. The long-term objective is to develop small molecule inhibitors that can be used for PM treatment.